New, Promising Treatments – AF 219, LiRIS, AQX-1125, GM-0111, LP-08
Patients constantly ask “Is there anything new?” Yes, Virginia, IC research is alive and well with teams from around the world exploring new treatments. Here’s our review of the most promising projects in the IC Pipeline!
Afferent Pharmaceuticals AF-219
Afferent Pharmaceuticals is developing a potential new pain medication for interstitial cystitis by targeting the nerves which are responsible for the transmission of pain in the bladder as well as other visceral organs. AF-219 is a selective, non-narcotic and orally administered P2X3 antagonist that targets the mechanism by which certain nerve fibers become hyper-sensitized and can lead to chronic and debilitating symptoms in diverse conditions.
In February 2015, Afferent released encouraging results from a Phase II clinical trial which showed that the AF- 219 improved symptoms of pain and urgency in patients with moderate to severe IC. In this randomized, double-blind, placebo-controlled Phase 2 clinical trial, patients were randomly assigned to either AF-219 or placebo treatment twice daily for four weeks, with AF-219 titrated from 50 mg to 300 mg in the first week and provided on a fixed-dose basis in weeks 2-4. Post-week 4, all patients were followed up for an additional two weeks.
Data from the study showed improvements in both pain and urinary urgency when compared to placebo. Safety and tolerability findings were similar between AF-219-treated patients and those receiving placebo, except that higher numbers of the AF- 219-treated patients experienced temporary changes in their sense of taste.
“Patients with IC/BPS often suffer debilitating symptoms that can interfere with daily commitments and social interactions,” commented Philip Hanno, M.D., lead clinical investigator in the IC/BPS study, and Professor of Urology in Surgery at the Hospital of the University of Pennsylvania. Dr. Hanno continued, “I am excited to be able to report clear clinical benefit and encouraging results in both pain and urinary urgency in this phase 2 IC/BPS trial. I look forward to further studies being planned in the future.”
One clear advantage of this medication is the lack of side effects caused by other pain medications, particularly drowsiness, brain fog and fatigue. Anthony Ford, Ph.D., Founder and Chief Scientific Officer of Afferent Pharmaceuticals, stated, “A key advantage of our approach is that the target P2X3 receptors have limited distribution beyond sensory nerves and no significant expression in the higher centers of the brain. AF-219 offers an alternative approach that we believe can limit the serious CNS side effects associated with many pain and urological treatments.” This marks nine clinical trials for this medication for IC, chronic cough and patients with idiopathic pulmonary fibrosis associated cough and breathlessness.
Allergan, Inc. LiRIS®
We’ve written about LiRIS® extensively in the past few years. Originally developed by Taris BioMedical, LiRIS® is a drug-device combination placed in the bladder for a two week period where it gradually releases lidocaine. Originally developed for the treatment of bladder pain, early research studies also found that LiRIS treatment healed some but not all Hunner’s Lesions. This represents a remarkable breakthrough in the treatment of what has been considered the most severe form of interstitial cystitis.
Allergan purchased LiRIS® from Taris in 2014. “Allergan has a longstanding history of delivering stockholder value by developing innovative medical treatments that address unmet medical needs,” said David E.I. Pyott, Chairman of the Board and Chief Executive Officer, Allergan. “Our work to develop BOTOX® (onabotulinumtoxinA) as a second-line treatment for overactive bladder (OAB) has made a significant difference for patients who suffer from this chronic condition. The acquisition of LiRIS® is an important addition to our growing urology pipeline and, if approved, will provide a local treatment for interstitial cystitis/ bladder pain syndrome, which is a debilitating bladder condition.”
Allergan is still seeking patients for their LiRIS/LiNKA Hunner’s lesion study. Click here for more information!
Source: Allergan Acquires LiRIS Program from TARIS Biomedical. Joint Press Release. August 13, 2014 – www.tarisbiomedical.com
A novel anti-inflammatory medication currently called AQX-1125 is being developed by Aquinox Pharmaceuticals, Inc. for interstitial cystitis and inflammatory diseases of the skin.
AQX-1125 is designed to reduce the immune cell activation that causes inflammation. The investigational medication works differently than other available anti-inflammatory medications. It is an activator of an enzyme in the body called SHIP1, which controls the PI3K cellular signaling pathway. If the PI3K pathway is overactive, immune cells can produce an abundance of pro-inflammatory signaling molecules and migrate to, and concentrate in, tissues, resulting in excessive or chronic inflammation. Therefore drugs that activate SHIP1 may reduce the function and migration of immune cells and have an anti-inflammatory effect.
Although the exact cause of IC is not totally understood, if inflammation is a component of the syndrome, AQX- 1125 may have the potential to reduce inflammation and therefore bladder pain.
Aquinox recently conducted a double blind, placebo controlled, Phase 2 clinical trial, the Leadership study, in order to determine if AQX-1125 could reduce bladder pain in IC patients. The study tested the effect of 6 weeks of treatment with once daily AQX-1125 (200 mg) versus placebo on reducing average daily pain. Sixty-nine patients from study centers in Canada and the United States enrolled in the trial. Study patients were women who had had a cystoscopy showing evidence of inflammation within the last 3 years. Patients also had to be experiencing pain at a level of at least 5 out of 10 on an 11-point (0-10) numeric rating scale, despite current therapy. Patients tracked their daily bladder pain scores and urinary symptoms over six weeks.
Approximately 49% of patients receiving AQX-1125 had a 2-point or greater reduction in average daily pain compared to 34% of patients who received placebo. The overall reduction in average pain with AQX-1125 and placebo on average daily pain recorded by diary was a 2.4 units compared to 1.4 units, a difference of 1.0 which was very close to being statistically significant (p=0.06). However the reduction in maximum daily pain recorded by diary was statistically significant (p=0.03) as was the pain reported to clinic staff.
Urinary symptoms were recorded throughout the study by having patients complete questionnaires and record their number of voids each day in the diary. The O’Leary-Sant IC Symptom and Problem Index combined score showed an improvement of 4.4 points more than placebo (p=0.008) and the Bladder Pain/IC Symptom Scale score improved by 4.8 points more than placebo (p=0.012). The results from these questionnaires demonstrate that urinary symptoms improved in patients who received AQX-1125. There was also a trend towards a reduction in the number of voids per day.
In Summer 2016, Aquinox launched a large scale Phase III study!
Source: Nickel JC, et al. A Phase II Study of the Efficacy and Safety of the Novel Oral SHIP1 Activator AQX-1125 in Subjects with Moderate to Severe Interstitial Cystitis/Bladder Pain Syndrome. J Urol 2016 Sep;196(3):747-54
GlycoMira Therapeutics GM-0111 and GM-1111
GlycoMira Therapeutics Inc. is a startup biotechnology company operating in the University of Utah Research Park. The company is focused on developing novel anti-inflammatory drugs based on glycobiology for applications in oral and urological health. They began their work with interstitial cystitis after receiving a Small Business Innovation and Research (SBIR) grant from the NIDDK in 2011 to study bladder inflammation and to develop a new treatment using semisynthetic glycosaminoglycan ethers (SAGEs). Glycosaminoglycans play an essential role in the construction of the bladder lining. Other GAG therapies currently in use for IC include heparin and chondroitin sulfate bladder instillations.
GlycoMira has developed two new medications, GM-0111 AND GM- 1111, which coat mucosal tissues and blocks multiple factors involved in inflammation. Collaborating urologist at the University of Utah, Dr. Siam Oottamasathien shared “The instillation of SAGEs has the potential to increase efficacy as well as reduce cost and side effects for women that are regularly catheterized with approved heparin or hyaluronic acid solutions,” said Dr. Oottamasthien. “Our ultimate goal to gain a better understanding of bladder inflammatory pathogenesis, and to provide a safe and effective new treatment for the many patients who suffer from PBS/IC.”
Dr. Oottamasathien’s research team has also focused on a peptide, LL-37, which occurs naturally during urinary tract infections and is known for its damaging effect to the bladder wall. Elevated levels of LL-37 damage the urothelium, a barrier of cells in the bladder that protects the underlying tissues from the urine. When stimulated with LL-37, these protective cells also release increased amounts of adenosine triphosphate (ATP) that mediates bladder contraction and causes pain. Dr. Lee and his coworkers showed that GM-0111 prevents cell death and also reduces ATP release from these cells. Of interesting note, they found high levels of LL-37 in the bladders of spina bifida patients and wonder if it could also be playing a role in interstitial cystitis. No studies have yet been done in humans for these treatments. The initial safety profile of GM-0111 is excellent with no irritation seen in tissues nor any toxicity when delivered systemically. Source: www.glycomira.com
Lipella Pharmaceuticals LP-08
Dr. Michael Chancellor has championed the use of liposomes in the treatment of interstitial cystitis for the past decade. As principal investigator, he has multiple studies under his belt demonstrating that these tiny, hollow spheres can penetrate deeply into the bladder wall and provide some benefit. Lipella Pharmaceuticals was launched to bring liposome based treatments to market for interstitial cystitis, overactive bladder, radiation cystitis and hemorrhagic cystitis.
LP-08 is Lipella’s lead product at this time and has been used in humans 138 times without any adverse events. In Sept. 2014, the results of a 14- patient clinical trial for LP-08 were released. The drug was administered directly into the bladder through one instillation a week for four weeks. At the end of the four weeks, patients showed an improvement in both pain and urgency. No adverse side effects were reported.
There is an active clinical trial seeking participants. Evaluation of Intravesical LP08 in Patients With Interstitial Cystitis/Painful Bladder Syndrome (NCT01393223) was launched in April 2015 to study two potential doses of the medication. They are currently seeking men and women with interstitial cystitis who have not responded to previous therapies and/or diet modification. The study is being conducted at Beaumont Hospital in Royal Oak, MI. If you’re interested, please contact: Contact: Jeannine Ramsey, RN, BSN at 440-221-9936.